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Immunophysical analysis of corneal neovascularization: mechanistic insights and implications for pharmacotherapy.

ABSTRACT: The cornea lacks adaptive immune cells and vasculature under healthy conditions, but is populated by both cell types under pathologic conditions and after transplantation. Here we propose an immunophysical approach to describe postoperative neovascularization in corneal grafts. We develop a simple dynamic model that captures not only the well-established interactions between innate immunity and vascular dynamics but also incorporates the contributions of adaptive immunity to vascular growth. We study how these interactions determine dynamic changes and steady states of the system as well as the clinical outcome, i.e. graft survival. The model allows us to systematically explore the impact of pharmacological inhibitors of vascular growth on the function and survival of transplanted corneas and search for the optimal time to initiatetherapy. Predictions from our models will help ongoing efforts to design therapeutic approaches to modulate alloimmunity and suppress allograft rejection.

SUBMITTER: Azimzade Y

PROVIDER: S-EPMC5610330 | biostudies-other | 2017 Sep

REPOSITORIES: biostudies-other

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Immunophysical analysis of corneal neovascularization: mechanistic insights and implications for pharmacotherapy.

Azimzade Youness Y Hong Jiaxu J Mashaghi Alireza A

Scientific reports 20170922 1

The cornea lacks adaptive immune cells and vasculature under healthy conditions, but is populated by both cell types under pathologic conditions and after transplantation. Here we propose an immunophysical approach to describe postoperative neovascularization in corneal grafts. We develop a simple dynamic model that captures not only the well-established interactions between innate immunity and vascular dynamics but also incorporates the contributions of adaptive immunity to vascular growth. We ...[more]

PMID: 28939878

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Project description:PurposeThe S100A protein family is involved in various inflammatory processes. Two of its members, S100A4 and A13, are thought to be pro-angiogenic in tumor development. This study examines whether S100A proteins are involved in the pathogenesis of inflammation-associated corneal neovascularization (CorNV).MethodsWe used 10-0 nylon suture--(S) or chemical burn (CB)--induced CorNV models for a microarray analysis of the genome-wide expression pattern. At different time points after suturing, we conducted histopathological examinations to detect the infiltration of inflammatory cells into the corneal stroma. Representative members of the S100A family (S100A4, S100A6, S100A8, S100A9, and S100A13), pro-inflammatory cytokines (IL-1β, IL-6, transforming growth factor β1, and MIP-2), and pro-angiogenic factors (fibroblast growth factor and vascular endothelial growth factor) were detected with reverse-transcription quantitative PCR (RT-QPCR). We used immunofluorescence to monitor neutrophil or macrophage infiltration and S100A8 or S100A9 protein deposition in neovascularized corneas. Antibody-mediated neutrophil depletion or S100A8 depletion in mice was performed to evaluate the role of neutrophils and S100A proteins in suture-induced corneal neovascularization (S-CorNV).ResultsMicroarray profiling revealed that S100A4, S100A6, S100A8, S100A9, and S100A13 were upregulated in both CorNV models, with S100A8 and S100A9 manifesting the most significant changes compared to the normal animals. An RT-QPCR assay of these S100A genes and cytokine genes in the S-CorNV corneas showed that the changes were time-dependent, reaching the apex at day 5. Immunofluorescence analysis demonstrated that neutrophils and macrophages produce S100A8 and S100A9. The depletion of neutrophils beginning one day before S-CorNV induction decreased disease severity and S100A8/S100A9 deposition in the neovascularized corneas. The extent of upregulation of other detected S100A genes and pro-inflammatory or pro-angiogenic genes was also decreased by neutrophil depletion. Subconjunctival administration of S100A8 antibodies also significantly inhibited the growth of vessels and inflammation in the S-CorNV model.ConclusionsWe determined that S100A proteins are involved in the inflammatory CorNV model and that S100A8 or S100A9 in particular might be employed as targets in managing diseases involving this pathological process.

Dataset Information

Immunophysical analysis of corneal neovascularization: mechanistic insights and implications for pharmacotherapy.

Publications

Immunophysical analysis of corneal neovascularization: mechanistic insights and implications for pharmacotherapy.

Similar Datasets

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